J Cancer 2013; 4(6):481-490. doi:10.7150/jca.6583 This issue

Research Paper

CBP Activity Mediates Effects of the Histone Deacetylase Inhibitor Butyrate on WNT Activity and Apoptosis in Colon Cancer Cells

Darina L Lazarova1, Christopher Chiaro1, Terrence Wong1, Eric Drago1, Anthony Rainey1,2, Shannon O'Malley1,3, Michael Bordonaro1✉

1. Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, USA
2. Marywood University, 2300 Adams Avenue, Scranton, PA 18509
3. The Pennsylvania State University, 201 Old Main, University Park, PA 16802

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Lazarova DL, Chiaro C, Wong T, Drago E, Rainey A, O'Malley S, Bordonaro M. CBP Activity Mediates Effects of the Histone Deacetylase Inhibitor Butyrate on WNT Activity and Apoptosis in Colon Cancer Cells. J Cancer 2013; 4(6):481-490. doi:10.7150/jca.6583. Available from https://www.jcancer.org/v04p0481.htm

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Mutations in the WNT/beta-catenin pathway are responsible for initiating the majority of colorectal cancers (CRCs). We have previously shown that hyperactivation of this signaling by histone deacetylase inhibitors (HDACis) such as butyrate, a fermentation product of dietary fiber, promotes CRC cell apoptosis. The extent of association between beta-catenin and the transcriptional coactivator CREB-binding protein (CBP) influences WNT/catenin signaling and, therefore, colonic cell physiology. CBP functions as a histone acetylase (HAT); therefore, we hypothesized that the modulation of WNT/catenin activity by CBP modifies the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that CBP affects the hyperinduction of WNT activity by butyrate. ICG-001, which specifically blocks association between CBP and beta-catenin, abrogates the butyrate-triggered increase in the number of CRC cells with high levels of WNT/catenin signaling. Combination treatment of CRC cells with ICG-001 and butyrate results in cell type-specific effects on apoptosis. Further, both butyrate and ICG-001 repress CRC cell proliferation, with additive effects in suppressing cell growth. Our study strongly suggests that ICG-001-like agents would be effective against butyrate/HDACi-resistant CRC cells. Therefore, ICG-001-like agents may represent an important therapeutic option for CRCs that exhibit low-fold hyperactivation of WNT activity and apoptosis in the presence of HDACis. The findings generated from this study may lead to approaches that utilize modulation of CBP activity to facilitate CRC therapeutic or chemopreventive strategies.

Keywords: CBP, ICG-001, colorectal cancer, WNT, butyrate, fiber.